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In vivo modulation of vincristine-induced neurotoxicity in Lymnaea stagnalis, by the ACTH(4–9)analogue Org 2766

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Summary

The use of the cytostatic agent vincristine (VCR) is limited by the occurrence of peripheral neuropathy. This side-effect is probably caused by interference with axonal microtubules. VCR depolymerizes microtubules and reacts with tubulin to form paracrystals. The potential of a neurotrophic ACTH(4–9) analogue, Org 2766, to counteract peripheral neuropathy caused by cytostatic agents is being investigated. In the present ultrastructural study, modulatory effects of Org 2766 on VCR-induced neurotoxicity were studied in vivo in neurons of the pond snail Lymnaea stagnalis, which has been shown previously to be a suitable test system to investigate neurotoxic side-effects of cytostatic agents. 24 h after treatment with VCR (25 μM), 68.4 ± 34.7 paracrystals were counted per cross-section of the cerebral commissure and the number of microtubules in the axons had been lowered to 46% of the control level. After a survival period of two weeks all paracrystals had disappeared. By that time, no recovery of the axonal microtubular system could be observed. However, post-treatment with Org 2766 (10−6 M) on day 6 after VCR treatment had induced a significant increase in the number of microtubules (+ 55%) on day 7. This beneficial effect lasted for the rest of the experimental period (14 days). These results suggest that post-treatment with Org 2766, i.e. after VCR clearance, can induce long-lasting beneficial effects on VCR-induced neurotoxicity in vivo.

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References

  1. Bender RA, Chabner BA: Tubulin binding agents. In: Chabner B (ed) Pharmacologic principles of cancer treatment. Saunders WB Company, Philadelphia, 1982, pp 256–262

    Google Scholar 

  2. Dustin P: Structure and Chemistry of Microtubules. In: Dustin P (ed) Microtubules. Springer-Verlag, Berlin, Heidelberg, New York, 1978, pp 23–70

    Google Scholar 

  3. Bunt AH: Paracrystalline inclusions in optic nerve terminals following intraocular injection of vinblastine. Brain Res 53: 29–39, 1973

    Google Scholar 

  4. Donoso JA, Green LS, Heller-Bettinger IE, Samson FE: Action of the vinca alkaloids vincristine, vinblastine and desacetyl vinblastine amide on axonal fibrillar organelles in vitro. Cancer Res 37: 1401–1407, 1977

    Google Scholar 

  5. Green LS, Donoso JA, Heller-Bettinger IE, Samson FE: Axonal transport disturbances in vincristine-induced peripheral neuropathy. Ann Neurol 1: 255–262, 1977

    CAS  PubMed  Google Scholar 

  6. Müller LJ, Moorer-van Delft CM, Zijl R, Doubos EW: Use of snail neurons in developing quantitative ultrastructural parameters for neurotoxic side effects of vinca antitumor agents. Cancer Res 50: 1924–1928, 1990

    Google Scholar 

  7. Schochet SS, Lampert PW, Earle KM: Neuronal changes induced by intrathecal vincristine sulfate. J Neuropathol Exp Neurol 27: 645–658, 1968

    Google Scholar 

  8. Sandler SG, Tobin W, Henderson ES: Vincristine-induced neuropathy. Neurology 19: 367–374, 1969

    CAS  PubMed  Google Scholar 

  9. Legha SS: Vincristine neurotoxicity — pathophysiology and management. Med Toxicol 1: 421–427, 1986

    Google Scholar 

  10. Jackson DV, McMahan RA, Pope EK, Case LD, Cooper MR, Kaplon MK, Richards F, Stuart JJ, White DR, Zekan PJ: Clinical trial of folinic acid to reduce vincristine neurotoxicity. Cancer Chemother Pharmacol 17: 281–284, 1986

    Google Scholar 

  11. Jackson DV, Pope EK, McMahan RA, Cooper MR, Atkins JN, Callahan RD, Paschold EH, Grimm RA, Hopkins JO, Muss HB, Richards F, Stuart JJ, White DR, Zekan PJ, Cruz JM, Spurr CL, Capizzi RL: Clinical trial of pyridoxine to reduce vincristine neurotoxicity. J Neuro-Oncol 4: 37–41, 1986

    Google Scholar 

  12. Jackson DV, Wells HB, Atkins JN, Zekan PJ, White DR, Richards II F, Cruz JM, Muss HB: Amelioration of vincristine neurotoxicity by glutamic acid. Am J Med 84: 1016–1022, 1988

    Google Scholar 

  13. Koning P de, Neijt JP, Jennekens FGI, Gispen WH: ORG 2766 protects from cisplatin-induced neurotoxicity in rats. Exp Neurol 97: 746–750, 1987

    Google Scholar 

  14. Gerritsen van der Hoop R, Koning P de, Boven E, Neijt JP, Jennekens FG, Gispen WH: Efficacy of the neuropeptide ORG 2766 in the prevention and treatment of cisplatin-induced neurotoxicity in rats. Eur J Cancer Clin Oncol 24: 637–642, 1988

    Google Scholar 

  15. Gerritsen van der Hoop R, Vecht CJ, Van der Burg MEL, Elderson A, Boogerd W, Heimans JJ, Vries EP, Van Houwelingen JC, Jennekens FGI, Gispen WH, Neijt JP: Prevention of cisplatin neurotoxicity with an ACTH(4–9) analogue in patients with ovarian cancer. N Engl J Med 322: 89–94, 1990

    PubMed  Google Scholar 

  16. Kooten B van, Diemen van HAM, Groenhout KM, Huijgens PC, Ossenkoppele GJ, Nauta JJP, Heimans JJ: A pilot study on the influence of a corticotrophin (4–9) analogue on vinca alkaloid-induced neuropathy. Arch Neurol 49: 1027–1031, 1992

    Google Scholar 

  17. Kiburg B, Loosdrecht van der AA, Schweitzer CM, Ossenkoppele GJ, Müller LJ, Heimans JJ, Huijgens PC: Effects of the ACTH(4–9) analogue, ORG 2766, on vincristine cytotoxicity in two human lymphoma cell lines, U 937 and U 715. Br J Cancer 69: 497–501, 1994

    Google Scholar 

  18. Koning P de, Gispen WH: ORG 2766 improves functional and electrophysiological aspects of regenerating sciatic nerve in the rat. Peptides 8: 415–422, 1987

    Google Scholar 

  19. Gerritsen van der Hoop R, Brakkee JH, Kapelle A, Samson M, Koning P de, Gispen WH: A new approach for the evaluation of recovery after peripheral nerve damage. J Neurosci Methods 26: 111–116, 1988

    Google Scholar 

  20. Müller LJ, Moorer-van Delft CM, Boer HH: The ACTH/MSH(4–9) analogue ORG 2766 stimulates microtubule formation in axons of central neurons of the snail Lymnaea stagnalis. Peptides 13: 769–774, 1992

    Google Scholar 

  21. Müller LJ, Kiburg B, Moorer-van Delft CM, Boer HH: Differential trophic effects of ORG 2766, an ACTH(4–9)/MSH(4–9) analogue, op peptidergic neurons and glial cells in the snail Lymnaea stagnalis. Peptides 15 (1): 143–149, 1994

    Google Scholar 

  22. Müller LJ, Moorer-van Delft CM, Kiburg B, Vermorken JB, Heimans JJ, Boer HH: Org 2766, an ACTH(4–9)/MSH(4–9) analogue, modulates vincristine-induced neurotoxicity in the snail Lymnaea stagnalis. Int J Oncol 5: 647–653, 1994

    Google Scholar 

  23. Rosenthal S, Kaufman S: Vincristine neurotoxicity. Ann Int Med 80: 733–737, 1974

    Google Scholar 

  24. Postma TJ, Benard BA, Huijgens PC, Ossenkoppele GJ, Heimans JJ: Long term effects of vincristine on the peripheral nervous system. J Neuro-Oncol 15: 23–27, 1993

    Google Scholar 

  25. Murry R, McLane J, Gruener D: Effects of ORG 2766, a neurotrophic ACTH(4–9) analogue, in neuroblastoma cells. Ann New York Acad Sci 679: 270–275, 1993

    Google Scholar 

  26. Windebank AJ, Smith AG, Russel JW: The effect of nerve growth factor, ciliary neurotrophic factor and ACTH analogs on cisplatin neurotoxicity in vitro. Neurology 44: 488–494, 1994

    Google Scholar 

  27. Müller LJ, Moorer-van Delft CM, Roubos EW, Boer HH: Neurons of the snail Lymnaea stagnalis as a model to study the neurotoxic side-effects of cytostatic compounds and the protective properties of ORG 2766, an ACTH-analogue. In: Kits KS, Boer HH, Joosse J (eds) Molluscan Neurobiology. Elsevier North Holland Publ Comp, Amsterdam, Oxford, New York, 1991, pp 227–234

    Google Scholar 

  28. Strand FL, Rose KJ, Zuecarelli LA, Kume J, Alves SE, Antonawich FJ, Garrett LY: Neuropeptide hormones as neurotrophic factors. Phys Rev 71(4): 1017–1046, 1991

    Google Scholar 

  29. Takanari H, Yosida T, Morita J, Izutsu K, Ito T: Instability of pleomorphic tubulin paracrystals artificially induced by vinca alkaloids in tissue-cultured cells. Biol Cell 70: 83–90, 1990

    Google Scholar 

  30. Casey EB, Jellife AM, Le Quesne PM, Millett YL: Vincristine neuropathy-Clinical and electrophysiological observations. Brain 96: 69–86, 1973

    CAS  PubMed  Google Scholar 

  31. Bender RA, Castle MC, Margileth DA, Oliverio VT: The pharmacokinetics of [3H]-vincristine in man. Clin Pharmacol Ther 22 (4): 430–438, 1977

    Google Scholar 

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Authors and Affiliations

  1. Graduate School Neurosciences, Amsterdam, Research Institute Neurosciences, Vrije Universiteit, The Netherlands

    Barbara Kiburg, Carry M. Moorer-van Delft, Jan J. Heimans, Peter C. Huijgens & Harry H. Boer

  2. Department of Biology, de Boelelaan 1087, 1081, HV Amsterdam, The Netherlands

    Barbara Kiburg, Carry M. Moorer-van Delft & Harry H. Boer

  3. Department of Neurology, Academisch Ziekenhuis der Vrije Universiteit, PO Box 7057, 1007, MB Amsterdam, The Netherlands

    Barbara Kiburg & Jan J. Heimans

  4. Department of Hematology, Academisch Ziekenhuis der Vrije Universiteit, PO Box 7057, 1007, MB Amsterdam, The Netherlands

    Peter C. Huijgens

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  1. Barbara Kiburg
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Kiburg, B., Moorer-van Delft, C.M., Heimans, J.J. et al. In vivo modulation of vincristine-induced neurotoxicity in Lymnaea stagnalis, by the ACTH(4–9)analogue Org 2766. J Neuro-Oncol 30, 173–180 (1996). https://doi.org/10.1007/BF00177268

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